Reversal of diastereofacial selectivity in the nucleophilic addition reaction to chiral N-sulfinimine and application to the synthesis of indrizidine 223AB

Article abstract of DOI:10.1016/S0040-4020(02)01250-4

Diastereoselective addition reaction of ester enolates and Grignard reagents to optically active N-sulfinimines was examined. Reversal of the diastereofacial selectivity was realized by using appropriate metal species, solvents and additives, and the β-amino esters (up to >98% de) and the homoallylic amines (up to >98% de) were obtained in good yields. β-Amino esters thus obtained were converted to the useful β-amino acids involving (R)-homoserine. Application to the synthesis of indrizidine alkaloids was also described.

Full text of DOI:10.1016/S0040-4020(02)01250-4

Tetrahedron 58 (2002) 9621–9628
Reversal of diastereofacial selectivity in the nucleophilic addition
reaction to chiral N-sulfinimine and application to the synthesis of
indrizidine 223AB
*
Yuji Koriyama, Akihiro Nozawa, Ryuuichirou Hayakawa and Makoto Shimizu
Department of Chemistry for Materials, Mie University, Tsu, Mie 514-8507, Japan
Received 15 August 2002; accepted 26 September 2002
Abstract—Diastereoselective addition reaction of ester enolates and Grignard reagents to optically active N-sulfinimines was examined.
Reversal of the diastereofacial selectivity was realized by using appropriate metal species, solvents and additives, and the b-amino esters (up
to .98% de) and the homoallylic amines (up to .98% de) were obtained in good yields. b-Amino esters thus obtained were converted to the
useful b-amino acids involving (R)-homoserine. Application to the synthesis of indrizidine alkaloids was also described. q 2002 Published
by Elsevier Science Ltd.
1. Introduction
Recently, we reported a reversal of diastereofacial
selectivity in the condensation reaction using an optically
active N-sulfinimine as a chiral source.1 Both diastereomers
of the b-amino esters were synthesized selectively from a
Scheme 1.
single chiral N-sulfinimine in good yields and diastereo-
meric excesses by changing the enolate metal species. The
obtained b-amino esters were converted to 3-unsubstituted
b-lactams, which are useful intermediates for the synthesis
of b-lactam antibiotics. Chiral sulfinimines are easily
prepared from commercially available reagents.2 This type
of chiral sulfinimines is one of the attractive building blocks
which have been recently employed in the asymmetric
synthesis of amines,3 b-amino acids, their ester derivatives,4
b-aminophosphonic acids,5 the taxolw side chain,6 its
fluorinated analog, isoquinoline derivatives,7 N-sulfinyl-
cis-aziridine-2-carboxylate,8 b-hydroxy-a-amino acids,9
and 2H-aziridinecarboxylates.10 Use of sulfoxides as chiral
synthons in asymmetric synthesis is now a well-established
and reliable strategy, and has been the subject of several
excellent reviews.11 In this paper, we describe the
nucleophilic addition reaction to a chiral N-sulfinimine
and application to the synthesis of indrizidine 223AB.
selectivity in the condensation reaction using an optically
active N-sulfinimine as a chiral source.1 We applied this
methodology to a diastereoselective addition reaction to the
chiral N-sulfinimine 1 possessing a furan ring. The starting
N-sulfinimine was prepared according to the literature
procedure (Scheme 1).12
2.1. Synthesis of b-amino ester
The asymmetric addition was carried out in the following
manner (Scheme 2): deprotonation of tert-butyl acetate with
LDA was followed by addition of N-sulfinimine 1 at 2788C.
In the case of transmetallation, metal halides such as
ClTi(OiPr)3 and ClAlEt2 were added to the lithium enolate,
and the resulting enolate was stirred for 30 min followed by
addition of the sulfinimine 1. The resulting reaction mixture
was stirred for several hours at 278 to 08C and quenched by
an addition of phosphate buffer solution. The crude addition
2. Results and discussion
We have already reported a reversal of diastereofacial
Keywords: diastereoselective; sulfinimin; asymmetric addition;
b-aminoester; homoallyl amine; alkaloid.
*
Corresponding author. Tel./fax: þ81-59-231-9413;
e-mail: mshimizu@chem.mie-u.ac.jp
Scheme 2.
0040–4020/02/$ - see front matter q 2002 Published by Elsevier Science Ltd.
PII: S0040-4020(02)01250-4

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Y. Koriyama et al. / Tetrahedron 58 (2002) 9621–9628
Table 1. Diastereoselective addition to N-sulfinimine 1
membered counterpart may be involved, which is respon-
sible for the formation of (3R)-isomer (Fig. 1). In each case,
the enolate approaches from the direction opposite to the
sterically congested p-tolyl group, forming the carbon–
carbon bond with high diastereoselectivity.
Metal
Additive (equiv.) Solvent Time Yield (%)
3S:3Ra
Li
–
THF
THF
THF
Et2O
THF
6 h
4 h
3 h
2 h
96
31
80
98
88
14:86
6:94
4:96
,1:99b
86:14c
AlEt2
Ti(OiPr)3
Ti(OiPr)3
K
–
HMPA (30)
2.2. Asymmetric allylation
5 min
a
Next, we applied this methodology to an asymmetric
allylation using allyl Grignard and allyl borane reagents
(Scheme 4). In the case of allyl Grignard reagent, the
combination of allyl magnesium bromide in CH2Cl2 gave
the best result (Table 2, 98% yield, S:R¼9:91). We also
succeeded in the reversal of the diastereofacial selectivity
by using allyl borane reagent. The allyl borane reagent was
prepared in situ, and the best result was obtained using
allylmagnesium chloride and BF3·OEt2 in Et2O (83% yield,
S:R¼.99:1).
Determined by HPLC analysis.
The reaction was quenched at 2788C.
The reaction was carried out at 21008C.
b
c
product was purified on preparative silica gel TLC which
was pre-treated with phosphate buffer. As shown in Table 1,
addition products 2 were obtained in good yield and
excellent selectivity. The diastereomeric ratio of the
b-amino ester obtained was determined by HPLC analysis.
The titanium enolate gave significantly good results over the
aluminum enolate. When the reaction was conducted in
Et2O, the best result was observed (98% yield,
3S:3R¼,1:99). We also observed the reversal of the
diastereofacial selectivity using the potassium enolate in
the presence of HMPA (88% yield, 3S:3R¼86:14).
Scheme 4. Asymmetric allylation.
The determination of the absolute configuration of the
addition product was carried out as follows (Scheme 3). The
b-aminoester 2 was reduced to the corresponding alcohol 3,
and removal of the chiral sulfinyl group was conducted with
TFA to give the amino alcohol 4, and the following
ozonolysis of the furan ring afforded (R)-homoserine.13 The
spectral data and optical rotation of the obtained (R)-
homoserine were identical with the literature data.13
Table 2. Diastereoselective allylation to N-sulfinimine 1
X
Additive Solvent Temperature (8C) Time Yield (%)
S:Ra
Br
–
–
Et2O 278–rt
CH2Cl2 278–0
12 h
4 h
5 min
5 h
4 h
94
98
31
99
98
83
15:85
9:91
92:8
14:86
12:88
.99:1
BF3·OEt2 Et2O
278
278–0
Cl
–
–
Et2O
CH2Cl2 278–0
278–240
BF3·OEt2 Et2O
2 h
a
Determined by HPLC analysis.
The present diastereoselectivity is also predictable by
chelation-control model (Fig. 2). In the case of the allyl
Grignard reagent, a four and six-membered metallacycle,
and/or a seven-membered counterpart may be involved,
which is responsible for the formation of (R)-isomer. In the
case of allyl borane reagent, a six-membered chair-like
transition state without chelation between the oxygen of
sulfinyl group and the borane atom may be involved. In each
case, the enolate approaches from the direction opposite to
the bulky p-tolyl group, forming the carbon–carbon bond
with high diastereoselectivity.
Scheme 3. Synthesis of (R)-homoserine.
The sense of diastereoselectivity is predictable by non-
chelation and chelation-control model. In the case of the
potassium enolate with HMPA in THF, asymmetric addition
would proceed through a non-chelation transition state
which is similar to the case with N-sulfinimine possessing a
1,3-dioxorane ring1 to give the (3S)-b-amino ester. On the
other hand, in the case of the lithium, aluminum, and
titanium enolates, a six-membered chair-like transition state
containing a four-membered metallacycle, and/or a seven-
Figure 2. Possible transition states.
The absolute configuration of the obtained homoallylamine
6 was determined in the following manner (Scheme 5). The
obtained homoallylamine 6 was oxidized with mCPBA to
give an N-tosyl derivative 7 and then the terminal olefin was
hydrogenated to the known N-tosyl amine 8. Comparison of
Figure 1. Possible transition states.

Y. Koriyama et al. / Tetrahedron 58 (2002) 9621–9628
9623
acetonitrile to give a cyclized compound 15 as an 87:13
mixture of epimers (Scheme 8). The sulfenyl group was
removed by Ra-Ni (W2) to afford the indrizidine 223AB.
The spectral data of the synthesized compound were
identical with those reported.19
Scheme 5. Determination of the absolute configuration.
the spectral data and optical rotation of the synthesized
compound to those in the literature established the
stereochemistry.14
3. Synthesis of indrizidine 223AB
Scheme 8.
Alkaloids containing the indolizidine skelton have a wide
and varied distribution within nature and demonstrate a
broad range of pharmacological activity, representing a
structural class of non-competitive blockers of neuro-
muscular transmission. Indrizidine 223AB15 is one of
these alkaloids isolated in minute quantity from the skin
extracts of the neo-tropical poison-dart frog (genus
Dendrobates) and has been the target of many synthetic
efforts. Application to the synthesis of indrizidine 223AB
was carried out as follows. N-tosyl amine 8 was cyclized to
dihydropyridinone 9 using mCPBA (Scheme 6). After ethyl
etherification of the alcohol moiety using triethyl ortho-
formate and BF3·OEt2, the reduction of the enone 10 was
carried out with NaBH4 to afford a mixture of a saturated
alcohol and its unsaturated counterpart. The subsequent
hydrogenation of the mixture gave 11.
4. Conclusions
We investigated diastereoselective addition reaction of ester
enolates, allyl Grignard, and allyl borane reagents to an
optically active N-sulfinimine, and we were able to
accomplish the reversal of the diastereofacial selectivity
by using the appropriate metal species, solvents, and
additives. Since the homoallyl amines and b-amino acids
obtained stereoselectively are useful precursors for the
synthesis of several bioactive compounds, this methodology
offers a convenient approach to such a useful class of
compounds.
5. Experimental
5.1. General aspects
Infrared spectra were determined on a JASCO IR-810
spectrometer. 1H NMR spectra were recorded with a JEOL
EX-270 spectrometer using tetramethylsilane as an internal
standard. Mass spectra were taken on a Waters micromass
ZQ. High performance liquid chromatography (HPLC) was
carried out using a Hitachi L-4000 detector and a Hitachi
L-6000 pump with a Merck Hibar column. Purification of
products was performed by column chromatography on
silica gel (Merck Silica Gel-60), and/or preparative TLC on
silica gel (Merck Kisel Gel PF254). Reagents and solvents
were used after purification or as purchased.
Scheme 6.
The hydroxy group of 11 was removed using the Barton
reaction16 to afford the 2,6-disubstituted piperidine 12. An
allyl group was introduced stereoselectively via tosyl
iminium salt,17 and the subsequent ozonolysis of the
terminal olefin and Wittig olefination gave the compound
13 which has a side chain necessary for the construction of
five-membered ring (Scheme 7).
5.2. Synthesis of b-amino ester
5.2.1. 4-Methylbenzenesulfinic acid furan-2-yl-
methyleneamide (1).12 To a solution of lithium bis(tri-
methylsilyl)amide at 2788C, which was freshly prepared
from
1,1,1,3,3,3-hexamethyldisilazane
(3.23 mL,
15.3 mmol) and n-butyllithium (1.44 M, 10.6 mL,
15.3 mmol), in 5 mL of THF was added a solution of (S)-
(2)-menthyl-p-toluenesulfinate (3 g, 10.2 mmol) in 15 mL
of THF. The reaction was warmed gradually and, then
stirred for 2 h at room temperature. The reaction mixture
was cooled to 08C, and to it was added a freshly distilled
furfural (1.27 mL, 15.3 mmol) and cesium fluoride (2.3 g,
15.3 mmol), and the whole was stirred overnight. The
reaction mixture was quenched by an addition of a
phosphate buffer solution at 08C, extracted with AcOEt,
Scheme 7.
The tosyl group of 13 was deprotected using sodium
naphthalenide18 to give a piperidine 14. After conversion to
the HCl salt, phenyl sulfenyl chloride was added to the
olefin moiety. The obtained crude addition product was
treated with potassium carbonate and sodium iodide in

9624
Y. Koriyama et al. / Tetrahedron 58 (2002) 9621–9628
dried over Na2SO4, and then evaporated in vacuo. The crude
product was purified by silica gel column chromatography
(pre-treated with 5% Et3N in hexane) eluenting with
hexane–ether¼1:1 to give the title imine as a light yellow
crystalline. Yield 1.99 g (8.5 mmol, 84%). The spectral data
are in accordance with those in the literature.12
water bath was added a solution of 3-furan-2-yl-3-(toluene-
4-sulfinylamino)propionic acid t-butyl ester (625.5 mg,
1.8 mmol, .98% de) in 15 mL of THF dropwise, and the
whole was stirred for 1 h at 08C. The reaction was quenched
by an addition of sat. Na2SO4 aq. The insoluble materials
were removed by filtration through a celitew pad and the
filtrate was evaporated in vacuo. The crude product was
purified by silica gel column chromatography (pre-treated
with 5% Et3N in hexane, hexane–AcOEt¼1:2) to give the
title compound as a colorless oil. Yield 471.5 mg
(1.69 mmol, 94%).
1H NMR (270 MHz, CDCl3) d 2.40 (s, 3H), 6.47 (dd, 1H,
J¼2.0, 2.0 Hz), 6.98 (d, 1H, J¼4.0 Hz), 7.23 (d, 2H,
J¼8.2 Hz), 7.57 (d, 1H, J¼2.0 Hz), 7.58 (d, 2H, J¼8.2 Hz),
8.50 (s, 1H); IR (neat) 1610, 1540, 1470, 1170, 790,
550 cm21; [a]2D3¼þ82.0 (c 0.93, CHCl3).
1H NMR (270 MHz, CDCl3) d 1.92–2.15 (m, 2H), 2.35 (s,
3H), 3.59–3.68 (m, 2H), 3.95 (brs, 1H), 4.70 (dd, 1H,
J¼6.4, 7.3 Hz), 5.27 (d, 1H, J¼6.6 Hz), 6.30, (m, 2H), 7.20
(d, 2H, J¼8.3 Hz), 7.36 (d, 1H, J¼1.0 Hz), 7.49 (d, 2H,
J¼7.9 Hz); IR (CHCl3) 3200, 2850, 1920, 1660, 1350, 970,
900, 540 cm21; MS (exact mass calcd for C14H17NO3S, m/e
279.0929, found m/e 279.0893).
5.2.2. 3-Furan-2-yl-3-(toluene-4-sulfinylamino)-pro-
pionic acid tert-butyl ester (3R-2, with the Li enolate).
To a solution of freshly prepared lithium diisopropylamide
(0.23 mmol) in 3 mL of THF was added a solution of t-butyl
acetate (26.1 mg, 0.23 mmol) in 3 mL of THF dropwise at
2788C under an argon atmosphere, and the mixture was
stirred for 30 min. To the reaction mixture was added a
solution of 4-methylbenzenesulfinic acid furan-2-
ylmethyleneamide (35 mg, 0.15 mmol) in 3 mL of THF,
and the mixture was allowed to warm to 08C during 6 h with
stirring. The reaction was quenched by an addition of a
phosphate buffer solution, extracted with AcOEt, dried over
Na2SO4, and concentrated in vacuo. The crude product was
purified by preparative silica gel TLC (pre-treated with
phosphate buffer) to afford the b-amino ester as a colorless
oil (diastereomeric mixture). Yield 50.1 mg (0.14 mmol,
96%); 3S:3R¼14:86.
3R: 1H NMR (270 MHz, CDCl3) d 1.37 (s, 9H), 2.41 (s, 3H),
2.75 (ddd, 2H, J¼6.0, 9.9, 2.6 Hz), 4.86 (dd, 1H, J¼6.1,
7.6 Hz), 4.99 (d, 1H, J¼7.6 Hz), 6.33 (d, 2H, J¼1.7 Hz),
7.25–7.39 (m, 3H), 7.60 (d, 2H, J¼8.3 Hz), IR (neat) 3175,
2975, 1730, 1360, 1170, 1060, 810, 740 cm21; MS (exact
mass calcd for C18H23NO4S, m/e 349.1348, found m/e
349.1393).
5.2.5. 3-Amino-3-furan-2-ylpropan-1-ol (4). To a solution
of 4-methylbenzenesulfinic acid (1-furan-2-yl-3-hydroxy-
propyl)amide (335.4 mg, 1.2 mmol) in MeOH cooled in an
ice water bath was added trifluoroacetic acid (273.7 mg,
2.4 mmol), and the whole was stirred for 4 h at 08C. The
reaction mixture was evaporated in vacuo to remove the
solvent and excess TFA. To the residue was added water,
and the mixture was basified with 1N NH3 aq (pH 9–10)
and extracted with AcOEt. The combined extracts were
dried over MgSO4 followed by solvent evaporation. The
crude product was purified on preparative silica gel TLC
(pre-treated with phosphate buffer, AcOEt–MeOH¼5:1£3)
to give the title amino alcohol as a colorless oil. Yield
136.6 mg (0.97 mmol, 81%).
1H NMR (270 MHz, CDCl3) d 1.85–2.04 (m, 2H), 3.27
(brs, 3H), 3.85 (t, 2H, J¼5.3 Hz), 4.14 (dd, 1H, J¼5.1,
3.3 Hz), 6.12 (d, 1H, J¼3.3 Hz), 6.31 (dd, 1H, J¼2.0,
1.3 Hz), 7.34 (dd, 1H, J¼0.7, 1.0 Hz). Despite several
attempts, a satisfactory mass analysis data could not be
obtained, and therefore, this material was used for the next
step without further characterization.
5.2.3. 3-Furan-2-yl-3-(toluene-4-sulfinylamino)-pro-
pionic acid tert-butyl ester (3R-2, with the Ti enolate).
To a solution of freshly prepared lithium diisopropylamide
(0.46 mmol) in 3 mL of Et2O was added a solution of t-butyl
acetate (52.3 mg, 0.45 mmol) in 3 mL of THF dropwise at
2788C under an argon atmosphere, and the mixture was
stirred for 30 min. A solution of 1 M chlorotitanium
triisopropoxide in hexane (0.46 mL, 0.46 mmol) was
added to the reaction mixture, which was stirred for
30 min. To the reaction mixture was added a solution of
4-methylbenzenesulfinic acid furan-2-ylmethyleneamide
(35 mg, 0.15 mmol) in 3 mL of THF, and the whole was
allowed to warm to 2458C during 2 h with stirring. The
reaction was quenched by an addition of a phosphate buffer
solution, extracted with AcOEt, dried over Na2SO4, and
concentrated in vacuo. The crude product was purified on
preparative silica gel TLC (pre-treated with phosphate
buffer) to afford the b-amino ester as a colorless oil
(diastereomeric mixture). Yield 51.3 mg (0.14 mmol, 98%);
3S:3R¼,1:99.
5.2.6. 3-Amino-5-hydroxypentanoic acid ((1)-5, homo-
serine).13 Ozone was bubbled into a solution of 3-amino-3-
furan-2-ylpropan-1-ol (73.6 mg, 1.52 mmol) in 5 mL of
MeOH at 2788C. The reaction was monitored by TLC.
After the starting material was consumed, argon gas was
bubbled into the reaction mixture, which was warmed
gradually to room temperature. Dimethyl sulfide (3 mL)
was added to the resulting mixture, which was stirred for 3 h
at room temperature. The reaction mixture was evaporated
under reduced pressure. The residue was partitioned
between hexane and water. After evaporation of water, the
residue was purified by ion exchange resin (Dowexw 50£2
100(Hþ), distilled water then 1N NH3 aq) to give (R)-
homoserine as a white solid. Yield 18.8 mg (0.16 mmol,
30%). The spectral data are in accordance with those in the
literature.13
5.2.4. 4-Methylbenzenesulfinic acid (1-furan-2-yl-3-
hydroxypropyl)amide (3). To a suspension of LAH
(82 mg, 2.16 mmol) in 3 mL of THF cooled in an ice
1H NMR (270 MHz, D2O) d 1.88–2.07 (m, 2H), 3.70–3.83
(m, 3H); [a]2D3¼þ8.8 (c 0.36, H2O); lit. [a]2D3¼þ8.8 (c 5,
H2O).

Y. Koriyama et al. / Tetrahedron 58 (2002) 9621–9628
9625
5.3. Asymmetric allylation
3250, 1500, 1450, 1320, 1160, 920, 660 cm21
,
[a]2D3¼274.8 (c 0.78, CHCl3); MS (Found: Mþ, 291).
5.3.1. 4-Methyl-benzenesulfinic acid (1-furan-2-ylbut-3-
enyl)amide (R-6, with allylmagnesium bromide). To a
solution of 4-methylbenzenesulfinic acid furan-2-
ylmethyleneamide (35 mg, 0.15 mmol) in 5 mL of ether
was added dropwise a solution of 0.52 M allyl magnesium
bromide in ether (0.81 mL, 0.42 mmol), and the whole was
stirred overnight during which it was allowed to warm to
room temperature. After cooling to 08C, the reaction
mixture was quenched by an addition of sat. NH4Cl aq,
extracted with AcOEt, dried over Na2SO4, and evaporated.
The crude product was purified on preparative silica gel
TLC (pre-treated with phosphate buffer, hexane–
ether¼1:1£3) to give the title homoallyl amine as a
colorless oil. Yield 38.8 mg (0.14 mmol, 94%);
S:R¼15:85 (determined by HPLC).
5.3.4. N-(1-Furan-2-ylbutyl)-4-methylbenzene sulfona-
mide (8).14 A mixture of 10% Pd/C (3.6 mg) and N-(1-
furan-2-ylbut-3-enyl)-4-methylbenzenesulfonamide(140 mg,
0.48 mmol)in EtOH was stirred for 6 h under a H2 atmosphere
(balloon). After the reaction was completed, the catalyst was
removed by filtration through a celitew pad, and the whole was
concentrated by evaporation followed by purification on
preparative silica gel TLC (pre-treated with phosphate buffer,
hexane–ether¼3:2£3) to give the title compound as a white
crystalline solid. Yield 141 mg (0.48 mmol, 99%). The
spectral data are in accordance with those in the literature.14
1H NMR (270 MHz, CDCl3) d 0.84 (t, 3H, J¼7.3 Hz),
1.06–1.37 (m, 2H), 1.74 (q, 2H, J¼7.6 Hz), 2.36 (s, 3H),
4.40 (q, 1H, J¼7.8 Hz), 5.44 (d, 1H, J¼8.6 Hz), 5.89 (d, 1H,
J¼3.3 Hz), 6.07 (dd, 1H, J¼1.8, 3.1 Hz), 7.10–7.18 (m,
3H), 7.62 (d, 2H, J¼8.6 Hz); IR (CHCl3) 2850, 1590, 1460,
1340, 1320, 980 cm21; [a]2D3¼257.5 (c 2.8, EtOH); MS
(Found: Mþ, 293).
1
R: H NMR (270 MHz, CDCl3) d 2.40 (s, 3H), 2.55–2.60
(m, 2H), 4.34 (d, 1H, J¼5.9 Hz), 4.59 (q, 1H, J¼6.5 Hz),
5.04–5.19 (m, 2H), 5.50–5.64 (m,1H), 6.33 (m, 2H), 7.29
(d, 2H, J¼8.1 Hz), 7.40 (m, 1H), 7.59 (d, 2H, J¼8.1 Hz); IR
(neat) 3200, 1190, 1160, 920, 810, 740 cm21; MS (exact
mass calcd for C15H17NO2S, m/e 275.0980, found m/e
275.1051).
5.4. Synthesis of indrizidine 223AB
5.4.1. 6-Hydroxy-2-propyl-1-(toluene-4-sulfonyl)-1,6-
dihydro-2H-pyridin-3-one (9). To a solution of N-(1-
5.3.2. 4-Methylbenzenesulfinic acid (1-furan-2-ylbut-3-
enyl)amide (S-6, with allylmagnesium chloride1BF3·
OEt2). To a solution of BF3·OEt2 (0.037 mL, 0.30 mmol) in
3 mL of ether cooled in an ice water bath was added 0.52 M
allylmagnesium chloride (1.73 m, 0.90 mmol) in ether
dropwise, and the whole was refluxed for 1 h. After cooling
to 2788C, a solution of 4-methylbenzenesulfinic acid furan-
2-ylmethyleneamide (35 mg, 0.15 mmol) was added
dropwise to the resulting mixture with stirring for 5 min.
Work-up and purification were done as in the above case.
furan-2-ylbutyl)-4-methylbenzenesulfonamide
(45 mg,
0.15 mmol) in 2 mL of CH2Cl2 was added a solution of
80% mCPBA (39.6 mg, 0.18 mmol) in 3 mL of CH2Cl2 at
08C, and the whole was stirred for 3 h, during which time the
mixture was allowed to warm to room temperature. The
reaction was quenched by an addition of sat. NaHCO3 aq at
08C, extracted with CH2Cl2, dried over Na2SO4, and then
evaporated. The crude product was purified on preparative
silica gel TLC (pre-treated with phosphate buffer, hexane–
ether¼3:2£3) to give the title compound as a white
crystalline solid. Yield 34.3 mg (0.11 mmol, 74%). The
spectral data are in accordance with those in the literature.14
Yield 34.4 mg (0.12 mmol, 83%),
S:R¼.99:1.
a colorless oil,
1
S: H NMR (270 MHz, CDCl3) d 2.39 (s, 3H), 2.63–2.80
(m, 2H), 4.42 (d, 1H, J¼6.9 Hz), 4.53 (q, 1H, J¼6.6 Hz),
5.05–5.20 (m, 2H), 5.63–5.78 (m, 1H), 6.12 (m, 1H), 7.26
(m, 3H), 7.63 (d, 2H, J¼8.3 Hz); MS (exact mass calcd for
C15H17NO2S, m/e 275.0980, found m/e 275.1050).
1H NMR (270 MHz, CDCl3) d 0.92 (t, 3H, J¼7.3 Hz), 1.29–
2.04(m, 4H), 2.39(s, 3H), 4.31(dd, 1H, J¼6.8, 8.4 Hz), 5.84–
5.92 (m, 2H), 6.77 (dd, 1H, J¼4.5, 10.4 Hz), 7.26 (d, 2H,
J¼8.3 Hz), 7.60 (d, 2H, J¼8.3 Hz); IR (CHCl3) 2650, 1730,
1580, 1360, 1000, 900 cm21; [a]2D3¼þ116.6 (c 0.69, EtOH).
5.3.3. N-(1-Furan-2-ylbut-3-enyl)-4-methylbenzene sul-
fonamide (7). To a suspension of 80% mCPBA (99 mg,
0.57 mmol) in 5 mL of CH2Cl2 was added a solution of
4-methylbenzenesulfinic acid (1-furan-2-ylbut-3-enyl)-
amide (123 mg, 0.44 mmol, .98% de) in 5 mL of CH2Cl2
at 2308C, and the whole was stirred until the temperature
reached 08C. The reaction was quenched by an addition of
sat. NaHCO3 aq, extracted with CH2Cl2, dried over Na2SO4,
and then evaporated. The crude product was purified on
preparative silica gel TLC (pre-treated with phosphate
buffer, hexane–ether¼3:2£3) to give the title compound as
a white crystalline solid. Yield 112.7 mg (0.39 mmol, 88%).
The spectral data are in accordance with those in the
literature.14
5.4.2. 6-Ethoxy-2-propyl-1-(toluene-4-sulfonyl)-1,6-
dihydro-2H-pyridin-3-one (10). To a solution of 6-
hydroxy-2-propyl-1-(toluene-4-sulfonyl)-1,6-dihydro-2H-
pyridin-3-one (417.5 mg, 1.35 mmol) in 25 mL of ether
cooled in an ice water bath was added triethyl orthoformate
˚
(1.1 g, 7.46 mmol) in the presence of MS4A (5 g), and then
to it was added seven drops of BF3·OEt2. The whole was
allowed to warm to room temperature during 3 h with
stirring. The reaction was quenched by an addition of Et3N
˚
(excess to BF3·OEt2). MS4A was removed by filtration
through a celitew pad, and the whole were washed with
AcOEt. The organic layer was washed with sat. NaCl aq,
dried over Na2SO4, and evaporated in vacuo. The crude
product was purified on preparative silica gel TLC (pre-
treated with buffer solution, hexane–ether¼3:2£3) to give
the title ethyl ether as a white crystalline solid. Yield
455 mg (1.34 mmol, 99%).
1H NMR (60 MHz, CCl4) d 2.38 (s, 3H), 2.57 (d, 2H,
J¼6.2 Hz), 4.45 (q, 1H, J¼7.1 Hz), 4.80–6.16 (m, 6H),
7.03–7.28 (m, 3H), 7.67 (d, 2H, J¼8.0 Hz); IR (CHCl3)

9626
Y. Koriyama et al. / Tetrahedron 58 (2002) 9621–9628
1H NMR (270 MHz, CDCl3) d 0.96 (t, 3H, J¼7.3 Hz), 1.26
(t, 3H, J¼6.9 Hz), 1.45–2.04 (m, 4H), 2.38 (s, 3H), 3.66–
3.78 (m, 1H), 4.01–4.12 (m, 1H), 4.25 (dd, 1H, J¼4.8,
10.1 Hz), 5.59–5.75 (m, 1H), 6.69 (dd, 1H, J¼4.5,
10.4 Hz), 7.23 (d, 2H, J¼8.1 Hz), 7.54 (d, 2H, J¼8.1 Hz);
be obtained, and therefore, this material was used for the
next step without further characterization.
5.4.5. 2-Ethoxy-6-propyl-1-(toluene-4-sulfonyl)-piper-
idine (12). A mixture of tributyltin hydride (0.34 mmol),
AIBN (cat. amt.), and dithiocarbonic acid O-[6-ethoxy-2-
propyl-1-(toluene-4-sulfonyl)piperidin-3-yl]ester S-methyl
ester (45 mg, 0.1 mmol) in toluene (3 mL) was refluxed
for 5 h. After cooling to 08C, the reaction was quenched by
an addition of sat. NaCl aq, extracted with AcOEt, dried
over Na2SO4, and then evaporated in vacuo. The crude
product was purified on preparative silica gel TLC (pre-
treated with phosphate buffer, hexane–ether¼12:1, multiple
development) to give the title compound as a white
crystalline solid. Yield 12.9 mg (0.04 mmol, 38%).
IR (CHCl3) 2950, 1680, 1340, 1170, 1020, 580 cm21
;
[a]2D3¼þ39.2 (c 0.59, EtOH); MS (exact mass calcd for
C22H35NO2S–OEt, m/e 292.1007, found m/e 292.1035).
5.4.3. 6-Ethoxy-2-propyl-1-(toluene-4-sulfonyl)-piper-
idin-3-ol (11). To a solution of 6-ethoxy-2-propyl-1-
(toluene-4-sulfonyl)-1,6-dihydro-2H-pyridin-3-one (610 mg,
1.8 mmol) in 25 mL of MeOH was added NaBH4, keeping
the temperature below 2308C. The reaction was monitored
by TLC. After the starting material was consumed, the
reaction was quenched by an addition of acetone (12.2 mL).
The solvent was removed under reduced pressure, and to the
residue was added AcOEt. The whole was washed with sat.
NaCl aq, dried over Na2SO4, and then concentrated in
vacuo. The crude product was purified by silica gel
column chromatography (hexane–ether¼1:1) to give a
mixture of saturated and unsaturated alcohols (570 mg). The
mixture was hydrogenated for 27 h under an atmosphere
(balloon) of hydrogen in EtOH in the presence of 10% Pd/C
(73 mg). After filtration through a celitew pad, the crude
product was purified by silica gel column chromatography
(hexane–ether¼1:1) to give the title compound as a
colorless crystalline. Yield 564.7 mg (1.65 mmol, 92%, 2
steps).
1H NMR (270 MHz, CDCl3) d 0.92 (t, 3H, J¼7.3 Hz), 1.20
(t, 3H, J¼7.1 Hz), 1.24–1.91 (m, 10H), 2.42 (s, 3H), 3.47–
3.59 (m, 1H), 3.71–3.87 (m, 2H), 5.23 (d, 2H, J¼2.3 Hz),
7.29 (d, 2H, J¼8.1 Hz), 7.70 (d, 2H, J¼8.1 Hz); IR (CHCl3)
2950, 1340, 1160, 920, 750, 660 cm21; MS (exact mass
calcd for C17H27NO3S, m/e 325.1712, found m/e 325.2100).
5.4.6. 2-Allyl-6-propyl-1-(toluene-4-sulfonyl)piperidine.
To a solution of 2-ethoxy-6-propyl-1-(toluene-4-sulfonyl)-
piperidine (250 mg, 0.76 mmol) in CH2Cl2 (20 mL) was
added
a
solution of allyltrimethylsilane (183 mg,
1.61 mmol) in CH2Cl2 (15 mL), and the mixture was cooled
to 2788C. To the resulting mixture was added a solution of
BF3·OEt2 (229 mg, 1.61 mmol) in CH2Cl2 (12.5 mL)
dropwise, and it was allowed to warm to 2208C during
3.5 h with stirring. The reaction was quenched by an
addition of sat. Na2CO3 aq, extracted with ether, dried over
Na2SO4, and then evaporated. The crude product was
purified on preparative silica gel TLC (pre-treated with
phosphate buffer, hexane–ether¼4:1£5) to give the title
compound as a colorless oil. Yield 211.9 mg (6.6 mmol,
87%).
1H NMR (270 MHz, CDCl3) d 0.95 (t, 3H, J¼7.1 Hz), 1.19
(t, 3H, J¼7.4 Hz), 1.23–1.90 (m, 9H), 2.42 (s, 3H), 3.25
(brs, 1H), 3.49–3.92 (m, 3H), 5.12 (d, 1H, J¼7.4 Hz), 7.29
(d, 2H, J¼8.1 Hz), 7.67 (d, 2H, J¼8.1 Hz); IR (CHCl3)
3500, 2950, 2860, 1340, 1160, 1000 cm21); MS (exact mass
calcd for C17H27NO4S, m/e 341.1661, found m/e 341.1900).
5.4.4. Dithiocarbonic acid O-[6-ethoxy-2-propyl-1-(tolu-
ene-4-sulfonyl)piperidin-3-yl]ester S-methyl ester. To a
stirred solution of NaH (337 mg, 9.84 mmol, 60% oil
dispersion) in THF was added a solution of 6-ethoxy-2-
1H NMR (270 MHz, CDCl3) d 0.93 (t, 3H, J¼7.3 Hz),
1.10–1.77 (m, 10H), 2.33–2.54 (m, 2H), 2.41 (s, 3H),
3.93–4.02 (m, 2H), 5.03–5.09 (m, 2H), 5.72–5.85 (m, 1H),
7.27 (d, 2H, J¼8.1 Hz), 7.71 (d, 2H, J¼8.1 Hz); IR (neat)
propyl-1-(toluene-4-sulfonyl)piperidin-3-ol
(560 mg,
1.64 mmol) in THF (40 mL), and the mixture was refluxed
for 1.5 h. After cooling to 08C, carbondisulfide (0.49 mL,
8.2 mmol) was added to the reaction mixture, which was
refluxed for 0.5 h. Methyl iodide (0.53 mL, 8.5 mmol) was
added dropwise to the resulting reaction mixture at 08C, and
it was refluxed for 0.5 h. The reaction was quenched by an
addition of sat. NaCl aq at 08C, extracted with AcOEt, dried
over Na2SO4, and evaporated. The crude product was
passed through a short silica gel column chromatography
(hexane–ether¼4:1) to give the title dithiocarbonate as a
pale yellow oil. Yield 691 mg (1.6 mmol, 98%). This
material was uded for the next step without further
purification.
2950, 2870, 1640, 1600, 1450, 1330, 1160, 660 cm21
;
[a]2D3¼27.5 (c 0.16, AcOEt); MS (exact mass calcd for
C18H27NO2S, m/e 321.1762, found m/e 321.2300).
5.4.7. 2-Hex-2-enyl-6-propyl-1-(toluene-4-sulfonyl)-
piperidine (13). Ozone was bubbled into a solution of 2-
allyl-6-propyl-1-(toluene-4-sulfonyl)piperidine (100 mg,
0.31 mmol) in CH2Cl2 (8 mL) at 2788C until the starting
material was consumed. The reaction was quenched by an
addition of dimethylsulfide (0.057 mL, 0.78 mmol), and
then warmed to room temperature. The resulting mixture
was evaporated in vacuo to remove the excess dimethyl-
sulfide.
[6-Propyl-1-(toluene-4-sulfonyl)piperidin-2-yl]-
1H NMR (270 MHz, CDCl3) d 0.95 (t, 3H, J¼5.8 Hz), 1.20
(t, 3H, J¼7.1 Hz), 1.34–2.19 (m, 8H), 2.42 (s, 3H), 2.54 (s,
3H), 3.54–3.60 (m, 1H), 3.83–3.89 (m, 1H), 4.38–4.42 (m,
1H), 5.02–5.11 (m, 1H), 5.15 (d, 1H, J¼3.3 Hz), 7.31 (d,
2H, J¼8.3 Hz), 7.76 (d, 2H, J¼8.3 Hz); IR (CHCl3) 2950,
1340, 1200, 1160, 1060, 960, 750 cm21. Despite several
attempts, a satisfactory mass spectral analysis data could not
acetaldehyde was obtained as a crude product (136 mg),
and used for the next reaction without further purification.
To a suspension of pentyltriphenylphosphonium bromide
(384 mg, 0.93 mmol) in Et2O (4 mL) was added n-butyl
lithium (1.52N, 0.61 mL) dropwise, and the whole was
refluxed for 2 h. To the resulting mixture was added a
solution of the aldehyde in Et2O (4 mL) at 08C, and the

Y. Koriyama et al. / Tetrahedron 58 (2002) 9621–9628
9627
whole was refluxed overnight. The reaction mixture was
cooled to 08C, quenched by an addition of water, extracted
with Et2O, dried over MgSO4, and then evaporated. The
crude product was purified on preparative silica gel TLC
(pre-treated with phosphate buffer solution, hexane–
Et2O¼8:1) to give the title olefin as a colorless oil. Yield
70.3 mg (0.18 mmol, 60%).
concentrated in vacuo. To the residue was added sat. NaCl
aq, and the whole was extracted with CHCl3. The combined
extracts were dried over MgSO4 and evaporated. The crude
product was purified on preparative silica gel TLC (pre-
treated with phosphate buffer, hexane–AcOEt¼10:1) to
give the title compound (an 87:13 mixture of epimers) as a
colorless oil. Yield 9.0 mg (0.027 mmol, 36%).
1H NMR (270 MHz, CDCl3) d 0.86–0.96 (m, 6H), 1.05–
1.73 (m, 14H), 1.98–2.05 (m, 2H), 2.36–2.49 (m, 2H), 2.41
(s, 3H) 3.99–3.86 (m, 2H), 5.31–5.48 (m, 2H), 7.26 (d, 2H,
J¼8.3 Hz), 7.71 (d, 2H, J¼8.3 Hz); IR (neat) 2920, 1720,
1450, 1340, 1160, 750, 660 cm21; [a]D23¼220.1 (c 0.37,
CHCl3); MS (exact mass calcd for C22H35NO2S, m/e
377.2388, found m/e 377.2306).
1H NMR (270 MHz, CDCl3) d 0.83–0.98 (m, 6H), 1.03–
1.45 (m, 10H), 1.53–1.82 (m, 8H), 2.18–2.28 (m, 1H),
2.54–2.69 (m, 2H) 3.33 (brs, 1H), 7.15–7.37 (m, 5H); MS
(exact mass calcd for C21H33NS, m/e 331.2334, found m/e
331.2266).
5.4.11. 3-Butyl-5-propyloctahydroindolizine; indrizidine
223AB.19 To a solution of 3-butyl-2-phenylsulfanyl-5-
propyloctahydroindolizine (9 mg, 0.027 mmol) in EtOH
was added Ra-Ni (W2) (200 mg suspended in EtOH), and
the whole was refluxed for 20 min. After cooling to room
temperature, the catalyst was removed by filtration through
a celitew pad. The filtrate was concentrated in vacuo to give
the title compound as a colorless oil. Yield 5 mg
(0.022 mmol, 83%). The spectral data are in accordance
with those in the literature.19
5.4.8. 2-Hept-2-enyl-6-propylpiperidine (14). To a sol-
ution of 2-hex-2-enyl-6-propyl-1-(toluene-4-sulfonyl)piper-
idine (65 mg, 0.17 mmol) in 1,2-dimethoxy ethane (DME)
was added a solution of sodium naphthalenide in DME,
freshly prepared from sodium and naphthalene, until the
color of the reaction mixture turned to light brown. The
resulting mixture was warmed to 08C, quenched by an
addition of sat. NaHCO3 aq, extracted with AcOEt, dried
over K2CO3, and then evaporated. The crude product was
purified on preparative silica gel TLC (pre-treated with
phosphate buffer, CH2Cl2–MeOH–Et3N¼10:1:0.2) to give
the title compound as a colorless oil. Yield 29 mg
(0.13 mmol, 75%).
1H NMR (270 MHz, CDCl3) d 0.86–1.00 (m, 6H), 1.15–
1.88 (m, 20H), 2.11–2.28 (m, 2H), 2.50–2.70 (m, 1H),
5.44–5.57 (m, 1H); IR (neat) 2950, 2850, 1780, 1466,
1120 cm21; MS (Found: Mþ, 223).
1H NMR (270 MHz, CDCl3) d 0.67–0.98 (m, 6H), 0.99–
1.11 (m, 2H), 1.23–1.40 (m, 9H), 1.61–1.75 (m, 2H), 1.80–
1.81 (m, 2H) 1.93–2.17 (m, 4H), 2.41–2.53 (m, 2H),
5.28–5.39 (m, 1H), 5.44–5.57 (m, 1H); IR (neat) 2920,
1450, 1370, 1330, 1120, 970 cm21; [a]D23¼212.1 (c 0.12,
CHCl3); MS (exact mass calcd for C15H29N, m/e 223.2300,
found m/e 223.2245).
Acknowledgements
We thank Professor D. H. Hua of Kansas State University
for very helpful discussions.
5.4.9. 2-(3-Chloro-2-phenylsulfenylheptyl)-6-propyl-
piperidine; hydrochloride. 2-Hept-2-enyl-6-propylpiper-
idine (29 mg, 0.13 mmol) was treated with HCl in MeOH.
After evaporation, CH2Cl2 was added to the residue, which
was cooled to 08C. To the above suspension was added a
solution of an excess phenylsulfenyl chloride (188 mg,
0.13 mmol) in CH2Cl2 and it was stirred for 10 min. The
reaction mixture was evaporated in vacuo to give a crude
product as a yellow solid. The stereochemistry and
regioselectivity of the obtained compound were not
determined at this stage, and it was used for the next
reaction without further purification. Yield 32.1 mg (crude).
References
1. Fujisawa, T.; Kooriyama, Y.; Shimizu, M. Tetrahedron Lett.
1996, 37, 3881–3884.
2. (a) Solladie, G. Synthesis 1981, 185–196. (b) Davis, F. A.;
Reddy, R. E.; Szewczyk, J. M.; Portonovo, P. S. Tetrahedron
Lett. 1993, 34, 6229–6232.
3. Annunziata, R.; Cinquini, M.; Cozzi, F. J. Chem. Soc., Perkin
Trans. 1 1982, 339.
4. Hua, D. H.; Miao, S. W.; Chen, J. S.; Iguchi, S. J. Org. Chem.
1991, 56, 4.
5. Lefebvre, I. M.; Evans, S. A. Phosphorus, Sulfur Silicon Relat.
Elem. 1999, 144, 397–400.
1H-NMR (270 MHz, CDCl3) d 0.81–0.98 (m, 6H), 1.01–
2.15 (m, 19H), 2.35–3.01 (m, 2H), 3.30–3.54 (m, 1H),
3.98–4.16 (m, 1H), 7.20–7.48 (m, 5H); MS (exact mass
calcd for C21H34ClNS, m/e 367.2100, found m/e 367.2003).
6. Davis, F. A.; Reddy, R. T.; Reddy, R. E. J. Org. Chem. 1992,
57, 6387.
7. (a) Davis, F. A.; Andemichael, Y. W. Tetrahedron Lett. 1998,
39, 3099–3112. (b) Davis, F. A.; Andemichael, Y. W. J. Org.
Chem. 1999, 64, 8627–8634.
5.4.10. 3-Butyl-2-phenylsulfenyl-5-propyloctahydro-
indolizine (15). To a solution of 2-(3-chloro-2-phenyl-
sulfenylheptyl)-6-propylpiperidine hydrochloride (30.1 mg,
0.075 mmol) in MeCN was added K2CO3 (83.5 mg,
0.34 mmol) and sodium iodide (80.5 mg, 0.3 mmol), and
the whole was heated at reflux for 5 h. The insoluble
material was removed by filtration and the filtrate was
8. For a review of chiral aziridine: Tanner, D. Angew. Chem. Int.
Ed. Engl. 1994, 33, 599.
9. (a) Davis, F. A.; Zhou, P.; Reddy, G. V. J. Org. Chem. 1994,
59, 3243. (b) Davis, F. A.; Zhou, P. Tetrahedron Lett. 1994,
35, 7525.
10. Davis, F. A.; Reddy, G. V.; Liu, H. J. Am. Chem. Soc. 1995,
117, 3651.

9628
Y. Koriyama et al. / Tetrahedron 58 (2002) 9621–9628
11. (a) Hua, D. H.; Chen, Y.; Millward, G. S. Sulfur Rep. 1999, 21,
211–239. (b) Solladie, G. Asymmetric Synthesis, Morrison,
J. D., Ed.; Academic: London, 1983; Vol. 2, pp 157–199.
(c) Walker, A. J. Tetrahedron: Asymmetry 1992, 3, 961–998.
(d) Kosugi, H. J. Synth. Org. Chem. Jpn 1987, 45, 472–480.
(e) Koizumi, T. J. Synth. Org. Chem. Jpn 1986, 44, 576–590.
12. Davis, F. A.; Reddy, R. E.; Szewczyk, J. M.; Reddy, G. V.;
Portonovo, P. S.; Zhang, H.; Fanelli, D.; Reddy, R. T.; Zhou,
P.; Carroll, P. J. J. Org. Chem. 1997, 62, 2555–2563.
13. (a) Natelson, S.; Natelson, E. A. Microchem. J. 1989, 40, 226.
(b) Natelson, S.; Pantazis, P.; Natelson, E. A. Clin. Chim. Acta
1994, 133, 229.
Stevens, R. V. J. Org. Chem. 1988, 53, 1871–1873. (d) Brandi,
A.; Cordero, F.; Querci, C. J. Org. Chem. 1989, 54,
1748–1750. (e) Machinaga, N.; Kibayashi, C. J. Org. Chem.
1992, 57, 5178–5189. (f) Muraoka, O.; Okumura, K.; Maeda,
T.; Tanabe, G.; Momose, T. Tetrahedron: Asymmetry 1994, 5,
317–320. (g) Momose, T.; Toshima, M.; Seki, S.; Koike, Y.;
Toyooka, N.; Hirai, Y. J. Chem. Soc., Perkin Trans. 1 1997,
1315.
16. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin
Trans. 1 1975, 1574.
17. (a) Hopman, J. C. P.; van der Berg, E.; Ollero, L. O.; Hiemstra,
H.; Speckamp, W. N. Tetrahedron Lett. 1995, 36, 4315.
(b) Shono, T.; Fujita, T.; Matsumura, Y. Chem. Lett. 1991, 81.
18. Robinnson, A. J.; Wyatt, P. B. Tetrahedron 1993, 49, 11329.
19. Nakagawa, Y.; Stevens, R. V. J. Org. Chem. 1988, 53,
1871–1873.
14. Zhou, W. S.; Lu, Z.-H.; Wang, Z.-M. Tetrahedron 1993, 49,
2641.
15. (a) Daly, J. W.; Brown, G. B.; Dwnmah, M. M.; Meyers, L. W.
Toxicon 1978, 16, 163. (b) Royer, J.; Husson, H. P.
Tetrahedron Lett. 1985, 26, 1515–1518. (c) Nakagawa, Y.;